A Japanese case of oculopharyngeal muscular dystrophy (OPMD) with PABPN1 c.35G > C; p.Gly12Ala point mutation

Abstract Background Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular dystrophy characterised by slowly progressive ptosis, dysphagia, and proximal limb muscle weakness. A common cause of OPMD is the short expansion of a GCG or GCA trinucleotide repeat in PABPN1 gene. Case presentation A 78-year-old woman presented with ptosis and gradually progressive dysphagia. Her son had the same symptoms. A physical examination and muscle imaging (MRI and ultrasound) showed impairment of the tongue, proximal muscles of the upper limbs, and flexor muscles of the lower limbs. Needle-electromyography (EMG) of bulbar and facial muscles revealed a myopathic pattern. Based on the characteristic muscle involvement pattern and needle-EMG findings, we suspected that the patient had OPMD. Gene analysis revealed PABPN1 c.35G > C point mutation, which mimicked the effect of a common causative repeat expansion mutation of OPMD. Conclusion We herein describe the first reported Japanese case of OPMD with PABPN1 point mutation, suggesting that this mutation is causative in Asians as well as in Europeans, in whom it was originally reported.

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Oculopharyngeal muscular dystrophy: a point mutation which mimics the effect of the PABPN1 gene triplet repeat expansion mutation

Journal of Medical Genetics ◽

10.1136/jmg.2005.037598 ◽

2005 ◽

Vol 43 (5) ◽

pp. e23-e23 ◽

Cited By ~ 13

Author(s):

D O Robinson

Keyword(s):

Muscular Dystrophy ◽

Point Mutation ◽

Repeat Expansion ◽

Triplet Repeat ◽

Oculopharyngeal Muscular Dystrophy ◽

Triplet Repeat Expansion ◽

Repeat Expansion Mutation ◽

Expansion Mutation

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Recent Progress in Oculopharyngeal Muscular Dystrophy

Journal of Clinical Medicine ◽

10.3390/jcm10071375 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1375

Author(s):

Satoshi Yamashita

Keyword(s):

Muscular Dystrophy ◽

Recent Progress ◽

Trinucleotide Repeat ◽

Late Onset ◽

Oculopharyngeal Muscular Dystrophy ◽

Limb Weakness ◽

Medical Needs ◽

Therapeutic Benefits ◽

Initial Symptoms ◽

Swallowing Problems

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset intractable myopathy, characterized by slowly progressive ptosis, dysphagia, and proximal limb weakness. It is caused by the abnormal expansion of the alanine-encoding (GCN)n trinucleotide repeat in the exon 1 of the polyadenosine (poly[A]) binding protein nuclear 1 gene (11–18 repeats in OPMD instead of the normal 10 repeats). As the disease progresses, the patients gradually develop a feeling of suffocation, regurgitation of food, and aspiration pneumonia, although the initial symptoms and the progression patterns vary among the patients. Autologous myoblast transplantation may provide therapeutic benefits by reducing swallowing problems in these patients. Therefore, it is important to assemble information on such patients for the introduction of effective treatments in nonendemic areas. Herein, we present a concise review of recent progress in clinical and pathological studies of OPMD and introduce an idea for setting up a nation-wide OPMD disease registry in Japan. Since it is important to understand patients’ unmet medical needs, realize therapeutically targetable symptoms, and identify indices of therapeutic efficacy, our attempt to establish a unique patient registry of OPMD will be a helpful tool to address these urgent issues.

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A polyalanine antibody for the diagnosis of oculopharyngeal muscular dystrophy and polyalanine-related diseases

MNI Open Research ◽

10.12688/mniopenres.12765.1 ◽

2017 ◽

Vol 1 ◽

pp. 1

Author(s):

Shawn J. Stochmanski ◽

François Blondeau ◽

Martine Girard ◽

Pascale Hince ◽

Daniel Rochefort ◽

...

Keyword(s):

Muscular Dystrophy ◽

Trinucleotide Repeat ◽

Late Onset ◽

Cag Repeat ◽

Spinocerebellar Ataxia Type ◽

Causative Mutation ◽

Oculopharyngeal Muscular Dystrophy ◽

Spinocerebellar Ataxia Type 3 ◽

Repeat Tract ◽

Repeat Expansions

Eighteen severe human diseases have so far been associated with trinucleotide repeat expansions coding for either polyalanine (encoded by a GCN repeat tract) or polyglutamine (encoded by a CAG repeat tract). Among them, oculopharyngeal muscular dystrophy (OPMD), spinocerebellar ataxia type-3 (SCA3), and Huntington’s disease (HD) are late-onset autosomal-dominant disorders characterized by the presence of intranuclear inclusions (INIs). We have previously identified the OPMD causative mutation as a small expansion (from 2 in normal to 7 in disease) of a GCG repeat tract in the PABPN1 gene. In addition, -1 ribosomal frameshifting has been reported to occur in expanded CAG repeat tracts in the ATXN3 (SCA3) and HTT (HD) genes, resulting in the translation of a hybrid CAG/GCA repeat tract and the production of a polyalanine-containing peptide. Previous studies on OPMD suggest that polyalanine-induced toxicity is very sensitive to the dosage and length of the alanine stretch. Here we report the characterization of a polyclonal antibody that selectively recognizes pathological expansions of polyalanine in PABPN1. Furthermore, our antibody also detects the presence of alanine proteins in INIs of SCA3 and HD patient samples.

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Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy

PLoS Genetics ◽

10.1371/journal.pgen.1010015 ◽

2022 ◽

Vol 18 (1) ◽

pp. e1010015

Author(s):

Cécile Ribot ◽

Cédric Soler ◽

Aymeric Chartier ◽

Sandy Al Hayek ◽

Rima Naït-Saïdi ◽

...

Keyword(s):

Muscular Dystrophy ◽

Muscle Atrophy ◽

Late Onset ◽

Oral Treatment ◽

Ubiquitin Proteasome System ◽

Proteasome Activity ◽

Functional Study ◽

Oculopharyngeal Muscular Dystrophy ◽

Ubiquitin Proteasome ◽

And Function

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.

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Hereditary ptosis of late onset: early observations on oculopharyngeal muscular dystrophy in Quebec by Roma Amyot

Neuromuscular Disorders ◽

10.1016/s0960-8966(97)00075-8 ◽

1997 ◽

Vol 7 ◽

pp. S12-S14 ◽

Cited By ~ 1

Author(s):

Pierre Duquette ◽

Normand Giard

Keyword(s):

Muscular Dystrophy ◽

Late Onset ◽

Oculopharyngeal Muscular Dystrophy

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Familial late onset oculopharyngeal muscular dystrophy.

Postgraduate Medical Journal ◽

10.1136/pgmj.57.663.41 ◽

1981 ◽

Vol 57 (663) ◽

pp. 41-43 ◽

Cited By ~ 5

Author(s):

D. A. Isenberg ◽

P. Kahn

Keyword(s):

Muscular Dystrophy ◽

Late Onset ◽

Oculopharyngeal Muscular Dystrophy

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A case report of rhabdomyolysis and osteofascial compartment syndrome in a patient with hypothyroidism and diabetes

BMC Endocrine Disorders ◽

10.1186/s12902-021-00868-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Lijue Ren ◽

Cuiying Wei ◽

Feng Wei ◽

Ruiting Ma ◽

Yan Liu ◽

...

Keyword(s):

Compartment Syndrome ◽

Lower Limbs ◽

Foot Drop ◽

Thyroid Peroxidase ◽

Muscle Involvement ◽

Case Presentation ◽

Albumin Infusion ◽

Facial Swelling ◽

Peroneal Nerve Injury ◽

Antithyroglobulin Antibodies

Abstract Background Hypothyroidism is frequent and has various forms of muscle involvement. We report the diagnosis and treatment of a case of rhabdomyolysis, bilateral osteofascial compartment syndrome (OCS) of the lower extremities, and peroneal nerve injury causing bilateral foot drop in a diabetic patient with hypothyroidism. Case presentation A 66-year-old man with diabetes for 22 years was admitted because of drowsiness, tiredness, facial swelling, and limb twitching for 2 months, and red and swollen lower limb skin for 3 days. Serum creatinine kinase (CK), CK-MB, myoglobin (Mb), blood glucose, and HbA1c were elevated. TSH, thyroid peroxidase antibodies, and antithyroglobulin antibodies were elevated. FT3 and FT4 were low. Urine was dark brown. He was diagnosed with hypothyroidism, rhabdomyolysis, and OCS. CK, CK-MB, and Mb returned to normal after treatment with thyroid hormone, insulin, albumin infusion, ceftriaxone, ulinastatin, and hemofiltration, and the redness and swelling of the lower limbs were relieved, but the patient developed dropping feet. The patient recovered well but had to undergo rehabilitation. Conclusion Hypothyroidism may induce rhabdomyolysis, OCS, and other complications. This case reminds us of the importance of screening for hypothyroidism and strengthens the clinicians’ understanding of the disease.

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